Composition based on hydrated lipidic lamelar phases or on liposomes containing at least one derivative of labdane, or a plant extract containing it; cosmetic or pharmaceutical, particularly dermatological composition containing it

ABSTRACT

The present invention relates to a novel composition based on hydrated lipidic lamellar phase or on liposomes and to a cosmetic or pharmaceutical, particularly dermatological composition incorporating it. The hydrated lipidic lamellar phases or the liposomes contain at least in part a derivative of labdane, or a plant extract containing it. The invention reduces hair loss and promotes hair growth.

This is a divisional application to U.S. Ser. No. 08/323,077 filed onOct.14, 1994, now U.S. Pat. No.5,510,173, which is itself a divisionalapplication to U.S. Ser. No.07/768,292, filed as PCT/FR90/00611 Aug. 14,1990, now U.S. Pat. No.5,384,126.

The present invention relates to compositions based on hydrated lipidiclamelar phases or on liposomes containing at least one derivative oflabdane, in particular a labd-14-ene, or a plant extract containing it,intended for the preparation of cosmetic or pharmaceutical, particularlydermatological compositions.

Labdanes, and in particular their unsaturated derivatives in 14position, called labd-14-enes, are diterpenes which are fairly widelydistributed in nature.

They are found in particular in different varieties of conifers(particularly pines), tobaccos, cistuses (in particular Cistusladaniferus, Cistus laurifolius), and Coleus (particularly Coleusforskohlii).

Coleus forskohlii represents one of the two hundred or so known speciesof Coleus, belonging to the family of Labiaceae and which are found inthe tropical and sub-tropical regions of Asia, Africa, Australia and thePacific islands. About nine species are catalogued in India. The tenprincipal varieties of Coleus are catalogued in Indian dictionaries andin particular "The Wealth of India, a dictionary of Indian Raw Materialsand Industrial Products, Raw Materials, volume II, Dehli 1950, pages308-309; the book entitled Indian Materia Medica by Dr. K. M.Nadkarni's, third edition revised and completed by A. K. Nadkarni in twovolumes, Volume I, page 372; the book entitled "The Flora of BritishIndia" by Sir J. D. Hooker, C. B., K. C., S. I. Volume IV entitled"Asclepiadae to Amarantaceae, pages 624 to 627.

The labdane derivatives to which the present invention refers are inparticular derivatives of general formula: ##STR1## in which: R₁ to R₂are identical or different and each represent a hydroxy group or a--O--COR₆ group in which R₆ represents an alkyl, alcoxy or alkenylradical possibly substituted, particularly by one or more hydroxy oramino groups,

R₃ represents an atom of hydrogen or a hydroxy group,

R₄ represents an atom of oxygen or the assembly ##STR2## R₅ representsan ethyl or vinyl radical.

Several derivatives of labdane responding to the above formula have beenextracted from various plants and in particular from the plant Coleusforskolii. Particular reference will be made to documents FR-2 336 138,FR-2 364 211 and EP-A-1-0 243 646 which describe forskoline (compound offormula I in which R₁ ═R₃ ═OH; R₂ ═OCOCH ₃ ; R₄ ═O; R₅ ═CH═CH₂),9-deoxyforskoline (compound of formula I in which R₁ ═OH, R₂ ═OCOCH₃ ;R₃ ═H; R₄ ═O; R₅ ═CH═CH₂) and coleforsine (compound of formula I inwhich R₂ ═R₃ ═OH; R₁ ═OCOCH₃ ; R₄ ═O; R₅ ═CH ═CH₂).

Other derivatives of labdane responding to the above formula have beenprepared by synthesis. Particular reference will be made to thefollowing documents: FR-2 372 822; S. V. BHAT et al., J. Chem. Soc.,Perkin Trans. 1982, volume 1, page 767; SV. BHAT et al., J. Med. Chem.1983, volume 26, pages 486-492; EP-A-252 482; EP-A-217 372; E. SEGUIN etal., Planta Medica, 1938, volume 54 No. 1, pages 4-6.

These documents disclose, in addition, that these compounds presentcertain pharmacological properties and in particular a hypotensive andcalming activity on the central nervous system.

Furthermore, document EP-A-O 120 165 describes the local use ofassociations comprising a β-stimulant and an α₂ -inhibitor, for thetreatment of fatty weight. This document cites forskoline by way ofexample of β-stimulant.

The present invention has for its object to solve the new technicalproblem consisting in the preparation of a novel formulation of acosmetic or pharmaceutical, particularly dermatological composition,comprising as active ingredient a labdane or a plant extract containingit and making it possible to potentialize the activity of thisingredient, in particular with respect to the stimulation of regrowth ofhair or the reduction in hair loss.

In fact, it has been discovered in totally unexpected manner, and thisconstitutes the basis of the present invention, that the labdanes or theplant extracts containing them, presented an activity stimulating theregrowth of hair and slowing down hair loss. In addition, it has beendiscovered that this activity, which remains weak for certain of thesecompounds, may be very considerably potentialized by their incorporationin hydrated lipidic lamelar phases or in liposomes.

In this way, according to a first aspect, the present invention concernsa composition based on hydrated lipidic lamelar phases, notablyliposomes, characterized in that said hydrated lipidic lamelar phases,notably liposomes contain at least in part a derivative of labdane, offormula I hereinafter, and/or a plant extract containing it. ##STR3## inwhich: R₁ and R₂ are identical or different and each represent a hydroxygroup or a --O--CO--R₆ --group in which R₆ represents an alkyl radicalhaving from 1 to 7 atoms of carbon, alkoxy radical having from 1 to 7atoms of carbon or alkenyl radical having from 1 to 7 atoms of carbon,possibly substituted by one or more hydroxy or ##STR4## groups in whichR₇ and R₈ each represent an atom of hydrogen, an alkyl radical havingfrom 1 to 4 atoms of carbon such as methyl or ethyl or representtogether and with the atom of nitrogen a heterocyclic radical such aspiperidino, morpholino, N'-methyl-piperazino;

R₃ represents an atom of hydrogen or a hydroxy group;

R₄ represents an atom of oxygen or the assembly ##STR5## R₅ representsan ethyl or vinyl radical.

According to a particular characteristic, the labdane derivative is acompound of formula (I) mentioned above in which:

R₁ represents the hydroxy group;

R₂ represents a hydroxy group or a --O--CO--R₆ group in which R₆represents an alkyl radical having from 1 to 4 atoms of carbon, analkoxy radical having from 1 to 4 atoms of carbon or an alkenyl radicalhaving 1 to 4 atoms of carbon, possibly substituted by one or twohydroxy groups or, at one end of chain, by a ##STR6## group in which R₇and R₈ each represent a methyl or ethyl radical or represent togetherand with the atom of nitrogen a hetero-cyclic radical such aspiperidino, morpholino, N'-methyl-piperazino:

R₃ represents the hydroxy group;

R₄ represents an atom of oxygen;

R₅ represents the vinyl radical.

The alkyl radicals, represented by R₆ -R₇ and R₈ in the above formulaemay be with linear, branched or cyclic chain.

An alkyl radical C₁ -C₇ is for example a methyl, ethyl, propyl,isopropyl, cyclopropyl, isobutyl, butyl, pentyl, neopentyl, preferablymethyl, ethyl or propyl radical.

On the other hand, the alkoxy and alkenyl radicals represented by R₆ inthe above formulae may also be with linear, branched or cyclic chain.

An alkoxy group with C₁ -C₇ is for example a methoxy, ethoxy, propoxy,isopropoxy, cyclopropoxy, butoxy, pentoxy, preferably methoxy, ethoxy orpropoxy group.

An alkenyl group with C₁ -C₇ is for example a vinyl, allyl, isopropenyl,butenyl, pentenyl, cyclohexenyl group.

This labdane derivative is advantageously chosen from the followingcompounds:

n^(o) 1 : forskoline

n^(o) 2 : 7-0-deacetyl-forskoline

n^(o) 3 : coleforsine

n^(o) 4 : 7-0-deacetyl-7-β-0-propanol-forskoline

n^(o) 5 : 7-0-deacetyl-7-β-0-(ethoxycarbonyl) -forskoline

n^(o) 6 : 7-0-deacetyl-7-β-0-0-(propoxycarbonyl)-forskoline

n^(o) 7 : 7-0-deacetyl-7-β-0-(2,3-dihydroxy-propanol)-forskoline

n^(o) 8 : 7-0-deacetyl-7-β-0-(3-methyl-2-butanoyl)-forskoline

n^(o) 9 : 7,0-deaetyl-7-β-0-4-(N'-methyl-piperazino)-butanoylΩ-forskoline

n^(o) 10 : 7-0-deacetyl-7-β-0-(4-morpholino-butanoyl)-forskoline

n^(o) 11 :6-β-0- 3-piperidino-propanolΩ-forskoline

n^(o) 12 :6-β-0-(piperidino-acetyl)-forskoline

These labdane derivatives are compounds of formula (I) above in which R₃═OH, R₄ O, R₅ ═CH═CH₃ and R₁ and R₂ have the significances figuring inTable I hereinbelow:

                  TABLE I    ______________________________________    n°        R.sub.1         R.sub.2    ______________________________________    1   OH              OCOMe    2   OH              OH    3   OCOMe           OH    4   OH              OCOEt    5   OH              OCOOEt    6   OH              OCOOPr    7   OH              OCOCH(OH)CH.sub.2 OH    8   OH              OCOCHC(CH.sub.3).sub.2    9   OH                         ##STR7##    10  OH                         ##STR8##    11         ##STR9##       OCOMe    12         ##STR10##      OCOMe    ______________________________________

According to another embodiment of the invention, or preparing such acomposition, an extract containing labdane derivative as definedpreviously is used, which is for example an extract of Coleus, inparticular an extract of Coleus forskolii, preferably an extract ofroots of the plant Coleus.

Advantageously, it is question of an organic extract of Coleus,particularly of roots of Coleus, preferably obtained by a processcomprising at least one step of extraction with a solvent selected fromthe group constituted by ethyl acetate, methanol, ethanol anddichloromethane.

However, use may be made, as solvent, of organic solvents such asaromatic hydroacarbons, dialkylics, halogenated aliphatic and aromatichydrocarbons, dialkylic ethers, dialkylketones, alkanols, carboxylicacids and their esters; or other solvents such as for exampledimethylformamide, dioxane, tetrahydrofurane and dimethylsulfoxide.

Among the solvents mentioned above, preferred solvents are benzene,toluene or xylene, methylene chloride, chloro-form, ethyl acetate,methanol or ethanol.

The ratio of the plant matter with respect to the extraction agent isnot critical and will generally be included between 1:5 and 1:20 partsby weight, and preferably 1:10 parts by weight about.

Extraction is effected at temperatures included between ambienttemperature and the boiling point of the solvent used for extraction.

A particularly advantageous technique of extraction is the so-calledtechnique of extraction employing Soxhlet. It may be advantageous, andin certain cases necessary, to evaporate the solvent, for example bylyophilization, and to take up the crude extracts with a view to apurification.

Within the framework of the present invention, extraction by alcohol isparticularly interesting, particularly at the end of procedure forobtaining the extract due to the usually hardly toxic character of thealcohols. A particularly advantageous alcohol is ethanol.

Another particularly interesting solvent is ethyl acetate because itfurnishes an extract rich in labd-14-ene derivative.

Particular variants of process are also described in the prior art, inparticular in the documents recalled in the preamble of the presentspecification.

The term "lipidic" in the expression "lipidic lamelar phases" covers allthe substances comprising a so-called fatty carbon chain, generallycomprising more than 5 atoms of carbon, this substance usually beingcalled "lipid".

According to the invention, for forming the lipidic lamelar phases,notably liposomes, use is made by way of lipid of amphiphilic lipids,i.e. constituted by molecules presenting a hydrophilic group which isequally well ionic or non-ionic and a lipophilic group, theseamphiphilic lipids being capable of forming lipidic lamelar phases,notably liposomes, in the presence of an aqueous phase, depending on thequantity of water in the mixture.

In particular, among these lipids, mention may be made of: thephospholipids, phosphoaminolipids, glycolipids, polyoxyethylenated fattyalcohols, the possibly polyoxyethylenated polyol esters. Such substancesare for example constituted by an egg or soya lecithin, aphosphatidylserine, a sphyngomyeline, a cerebroside or an oxyethylenatedpolyglycerol glycerol stearate.

According to the invention, a lipidic mixture is preferably used,constituted by at least one amphiphilic lipid and at least onehydrophobic lipid such as sterol, like cholesterol or β-sitosterol. Thequantity, expressed in mols, of hydrophobic lipid must generally not begreater than the quantity of amphiphilic lipid, and preferably, it mustnot be greater than 0.5 times this quantity.

The incorporation in hydrated lipidic lamelar phases, notably liposomes,of the compounds or extracts containing these compounds, used inaccordance with the present invention, may be effected in accordancewith known techniques of preparation, described for example in U.S. Pat.No. 4,508,703, and possibly in combination with U.S. Pat. No. 4,621,023.

According to a second aspect, the present invention concerns a cosmeticor pharmaceutical, particularly dermatological logical composition,intended in particular to promote regrowth of hair or to reduce hairloss or to promote pigmentation of the epidermis or to prevent gray hairappearing or for treating gray hair, characterized in that it comprises,by way of active ingredient, at least one derivative of labdane, offormula I mentioned above, and/or an extract of plants containing it, atleast partly incorporated in hydrated lipidic lamelar phases, notablyliposomes.

The cosmetic or pharmaceutical, particularly dermatological compositionsaccording to the present invention will generally be produced from thecompositions based on hydrated lipidic lamelar phases, notably liposomesdescribed hereinbefore.

The concentration of labdane derivative or of extract containing it,incorporated at least in part in hydrated lipidic lamelar phases,notably liposomes, will preferably be included between 0.0001% and 1% byweight, preferably still between 0.01% and 0.1% by weight, with respectto the total weight of the cosmetic or pharmaceutical composition.

These proportions are understood to be by dry weight when it is questionof plant extracts.

According to a variant embodiment, a cosmetic or pharmaceutical,particularly dermatological composition according to the inventioncomprises in addition at least one other active substance, at anefficient concentration, selected from xanthines, vitamins, particularlyvitamin B's, tyrosine or its derivatives such as for example glucosetyrosinate, quinine or its derivatives, rubefacients such as methylnicotinate, a supernatant of culture of fibroblasts of papillae, asdefined in document EP-A-272 920, keratin hydrolysates, oligo-elementssuch as zinc, selenium, copper, 5-α-reductase inhibitors such as:progesterone, cyproterone acetate, Minoxidil, azelaic acid and itsderivatives, a 4-methyl-4-azasteroid, in particular17-β-N,N-diethyl-carbamoyl-4-methyl-4-aza-5-α-androstan-3-one, or anextract of Serenoa repens, said active substance possibly beingincorporated at least in part in said hydrated lipidic lamelar phases,notably liposomes.

The cosmetic compositions according to the present invention may beapplied topically to promote regrowth of hair, to reduce hair loss, orto promote pigmentation of the epidermis or prevent gray hair fromappearing or for treating gray hair, in particular in compositions inthe form of creams, gels or lotions intended for topical application onthe hair.

Under this aspect, the present invention also provides a process fortreating the hair intended in particular to promote regrowth thereof andto reduce drop thereof or to promote pigmentation of the epidermis orprevent gray hair from appearing or for treating gray hair,characterized in that it comprises the application, in an efficientquantity to produce the effect of regrowth of the hair or for reducingloss thereof, to promote pigmentation of the epidermis or prevent grayhair from appearing or to treat gray hair, of at least one compositionbased on hydrated lipidic lamelar phases, notably liposomes, as definedpreviously, possibly in association with a pharmaceutically orcosmetically acceptable excipient, vehicle or support.

It should be noted that the expression "at least partly incorporated inhydrated lipidic lamelar phases, notably liposomes" is understood tomean in the present description and in the Claims, that the derivativeof labdane or the extract of plants containing it is combined withhydrated lipidic lamelar phases, notably liposomes, whatever the form ofthis combination.

However, it is clear that a preferred combination according to theinvention resides in the incorporation, or even the encapsulation, inthe hydrated lipidic lamelar phases, notably liposomes. However, it isnot necessary that the whole of the active principle be incorporated orencapsulated in order to obtain the desired effect.

According to another aspect, the invention further provides a processfor manufacturing a cosmetic or pharmaceutical, particularlydermatological composition intended to promote regrowth of hair or todelay hair loss, to promote pigmentation of the epidermis or to preventgray hair from appearing or to treat gray hair, characterized in that itcomprises in the first place the incorporation of at least one labdaneand/or a plant extract containing it, at least in part in hydratedlipidic lamellar phases, notably liposomes, then the mixture thereof ina pharmaceutically or cosmetically acceptable excipient, vehicle orsupport.

Under this latter aspect, the invention concerns the use of acomposition based on hydrated lipidic lamelar phases, notably liposomessuch as defined hereinabove for the preparation of a cosmetic orpharmaceutical, particularly dermatological composition, intended forthe treatment of hair, particularly for promoting regrowth of the hairor for reducing hair loss and for preventing gray hair from appearing orfor treating gray hair.

Other purposes, characteristics and advantages of the invention willappear more clearly upon reading the following explanatory descriptionmade with reference to several Examples given solely by way ofillustration and which consequently in no way limit the scope of theinvention.

In the Examples, the percentages are expressed by weight, unlessindicated to the contrary.

When it is question of plant extracts, the weights indicated are dryweights unless indicated to the contrary.

BRIEF DESCRIPTION OF THE DRAWING

The accompanying single FIGURE reports test results of the product ofthe present invention on the pilary cycle of Sprague-Dawley rats withthe percentage of hairs in anagenous phase comprising the Y-axis as afunction of the number of days on the X-axis as reported in detail inexample.

EXAMPLE 1

Preparation of a suspension of liposomes containing a labd-14-enederivative

In 25 ml of a mixture of dichloromethane and of methanol in volumetricproportion 4:1, are dissolved 0.398 g of soya lecithin and 0.002 g offorskoline (1α, 6β,9α-trihydroxy-7β-acetoxy-8,13-epoxy-labd-14-en-11-one).

The solution is evaporated in a rotating flask under reduced pressure atabout 45° C.

The lipidic film obtained is taken up with stirring in about 19.6 ml ofaqueous solution constituted by a phosphate PBS buffer.

A suspension of lipidic vesicles or liposomes is obtained, which is thentreated with ultra-sounds for 15 minutes at 4° C. with a power of 150 W.

A suspension of liposomes is thus obtained, of substantially homogeneoussize, of the order of 139 nm. This suspension contains about 0.01% offorskoline, incorporated in the lipidic phase of the liposomes.

If desired, this suspension may be gelified, for example by mixing itwith an equivalent volume of a gel of Carbopol 940® prepared inconventional manner.

EXAMPLE 2

Obtaining of an extract of Coleus from Coleus forskolii

60 g of dried, ground roots of Coleus forskolii are extracted withSoxhlet with 600 ml of solvent. Extraction is effected at boilingtemperature of the solvent with an ever-renewed solvent.

The mean yield of extraction is as follows, expressed in dry weight:

a) Ethanol/water mixture (80/20 v/v): about 9.2 to 9.5 g (extract 2A)

b) Ethyl acetate: about 1.5 g (extract 2B)

c) Dichloromethane: about 4 g (extract 2C).

EXAMPLE 3

Incorporation of an extract of Coleus forskolii in hydrated lipidiclamelar phases or in liposomes

An extract of Coleus forskolii obtained in accordance with Example 2 isincorporated in hydrated lipidic lamelar phases or in liposomes inaccordance with the technique of preparation described in Example 1.

The preparation of the liposomes is for example as follows:

The following are weighed:

soya lecithin 0.9 g

β-sitosterol 0.1 g

lyophilized Coleus extract (extract 2B)0.025 g

These constituents are dissolved in a mixture constituted by 100 ml ofdichloromethane and 25 ml of methanol.

The mixture thus obtained is evaporated in a rotating flask at atemperature of 45° C. under reduced pressure.

The lipidic film thus obtained is then taken up and dispersed withstirring in distilled water qsp 50 g, at ambient temperature for 2hours.

The suspension of lipidic vesicles obtained is then homogenized by anultra-sound treatment for 30 minutes at 4° C., at a power of 150 W.

The mean size of the liposomes thus obtained is about 212 nm.

This suspension is then gelified by mixing it with 50 g of Carbopol 940®gel at 1.25% prepared separately in conventional manner. About 100 g arethus obtained of a gelified suspension of liposomes encapsulating theextract of Coleus forskolii, whose concentration is about 0.025% withrespect to the total weight of the suspension.

EXAMPLES 4 to 9

By following the experimental process described in Example 1,suspensions of liposomes were prepared from the following compositions:

EXAMPLE

    ______________________________________    soya lecithin           2 g    β-sitosterol       0.05 g    Coleus extract (extract 2B)                            0.01 g    distilled water, qsp    50 g    ______________________________________

EXAMPLE 5

    ______________________________________    lecithin of egg        1.8 g    cholesterol            0.1 g    extract of Coleus (extract 2A)                           0.02 g    distilled water, qsp   50 g    ______________________________________

EXAMPLE 6

    ______________________________________    lecithin of soya       2 g    extract of Coleus (extract 2C)                           0.035 g    distilled water, qsp   50 g    ______________________________________

EXAMPLE 7

    ______________________________________    lecithin of soya       2 g    β-sitosterol      0.1 g    extract of Coleus (extract 2B)                           0.03 g    distilled water, qsp   50 g    ______________________________________

EXAMPLE 8

    ______________________________________    lecithin of soya       2 g    progesterone           0.001 g    extract of Coleus (extract 2A)                           0.0275 g    distilled water, qsp   45 g    ______________________________________

EXAMPLE 9

    ______________________________________    lecithin of soya       2 g    extract of Coleus (extract 2C)                           0.025 g    extract of Serenoa repens                           0.01 g    distilled water        50 g    ______________________________________

EXAMPLE 10

Evidencing of an hair loss preventing activity on the growth of the hair

The hair loss preventing activity on the growth of the hair is evidencedby studying the activity of the products according to the invention onthe pilary cycle of Sprague Dawley rats aged 23 days. The rats areshaved, in the lower part of their back, on the 24th day.

From the 25th day and up to the 65th day, 6 days out of 7, the productsto be tested are then applied at a dose ranging from 0.5 ml to 2 ml as afunction of the weight gain of the animals.

At substantially regular intervals of time (every 3 days about), a smalltuft of at least 10 hairs is removed, with tweezers, on the left-handside of the animal: at the level of the flank.

The percentage of hairs in anagenous phase (phase of growth) is thencounted as a function of time. Identification of the hairs in anagenousphase is effected by microscopic observation of the lower end of thehair. The base of the hairs in anagenous phase is fine, as the livingpart has remained in the dermis, whilst the base of the hairs intelogenous phase (rest phase) is in club form. The hairs in catagenousphase (intermediate phase of regression) are always very few.

The study is made on 30 rats distributed in 3 batches of 10 animals. Thefirst batch receives the product of Example 3. The second receives analcoholic solution of the same extract of Coleus at the sameconcentration of 0.025%. The third batch is the control batch receivingno product.

The results of this trichokinetic study are given in the accompanyingsingle FIGURE.

In this FIGURE, the percentage of hairs in anagenous phase is plotted onthe y-axis and the number of days on the x-axis.

The curve joining the triangles whose apex is directed upwardlycorresponds to the results obtained with liposomes incorporating 0.025%of extract of Coleus, and prepared according to Example 3.

The curve joining the triangles whose apex is directed downwardlycorresponds to the results obtained with the control batch.

The curve joining the circles corresponds to the results obtained withan extract of Coleus in alcohol, in the free state, at the sameproportion of 0.025% by weight, with respect to the total weight of thecomposition.

It will be observed that the number of hairs in anagenous phaseincreases much more rapidly in the batch receiving the extract of Coleusin liposomes according to the invention, than in the one receiving thealcoholic solution of extract of Coleus (respectively 65% and 25% on day37). It will also be observed that the anagenous phase extends longer.

On the other hand, if the curve corresponding to the alcoholic solutionof extract of Coleus is compared with the control curve, no reallysignificant difference is observed.

In this way, it is clear that the extracts of Coleus incorporated in theliposomes, according to the invention, by the extension of the durationof the anagenous phase, very clearly slow down hair loss and promoteregrowth thereof.

EXAMPLE 11

Measurement of the pigmenting activity of an extract of Coleusforskohlii incorporated in liposomes on the cutaneous pigmentation inthe guinea pig

Protocol:

The study was made on a batch of 10 three-coloured guinea pigs.

Before and during the experimentation, the right and left flanks of theguinea pigs were carefully shaved, every day for the first 5 days(period of exposure to U.V.), then every 2 days until the end of thestudy.

For each animal, there are determined on each flank comparably pigmentedmarks, most often of light brown appearance. On one of the two flankstaken at random, about 0.5 g of product to be tested or of controlproduct, depending on the batch, is applied 10 mins. before exposure toultraviolet rays, the other flank being exposed "bare" by way ofcontrol.

The application of the products to be tested is effected as from thefirst day of exposure until the animal is sacrificed.

Exposure to ultraviolet radiation is effected by means of a solarsimulator delivering 86% of U.V.A. and 14% U.V.B during the first 5 daysof the experiment, at a rate of 5 mins. the first day, 10 mins. thesecond day, 15 mins. the third day and 20 mins. the fourth and fifthdays.

The animals are sacrificed 12 days after the last exposure, and acutaneous biopsy is effected.

A fragment of skin is thus re-moved from the non-treated but exposedflank as well as from the other treated and exposed flank.

A histological examination is then made of the cutaneous fragments.

This examination comprises: on the one hand, the study of themelanogenesis by the Argentaffine de Fontana method on sections of 4>m(Techniques d'histologie, Professor Chevreau, Ed. Maloine, 1977, page157), on the other hand, the assessment of the thickness of theepidermis on sections of 4>m coloured in accordance with the trichomicmethod of Masson.

The study of the thickness of the epidermis and of the intensity of themelanogenesis makes it possible to assess a tanning effect or moreexactly the activation of the process of melanogenesis.

To study the melanogenesis, two zones taken at random from a pigmentedmark are examined, in which 25 malpigian cells are noted and among thelatter the "activated" melanocytes are counted, i.e. containing melaninein a cluster. The activation of the process of melanogenesis is thenexpressed in percentage of activated cells from the average of these twovalues.

On these same zones, the quantity of melanine in the other layers of theepidermis is examined and this quantity is assessed overall in a scalewith five values varying from 0 to 4 depending on whether the quantityof melanine formed is zero, low, average, large or very large.

Table I shows the results of the histological study giving thepercentage of activation and making it possible to assess the variationsin the quantity of melanine formed (average values on the scale definedhereinabove), of the thickness of the epidermis (expressed in >m).

The product tested is constituted by an extract of Coleus with ethylacetate according to Example 2b, incoporated in liposomes according toExample 3, but titrating 0.0284% of Coleus extract instead of 0.025%.

                  TABLE I    ______________________________________                       Control                             Treated                       flank flank    ______________________________________    % Activation         33.40   85.30    Quantity of melanine 0.16    2.39    Thickening of the epidermis in > m                         8.32    14.10    ______________________________________

From Table I it may be ascertained that the extract of Coleusincorporated in liposomes according to the invention is active onmelanogenesis. A reading of the histological sections of the treatedflanks shows a very high rate of activated melanocytes presentingrhizomic forms, and a considerable migration of the grains of melaninesin the epidermis.

These results therefore clearly confirm the activity of the extracts ofColeus incorporated in liposomes according to the invention on theactivation of the melanocytes.

Various examples of formulation of cosmetic or pharmaceuticalcompositions promoting regrowth of the hair and/or reducing hair dropand/or preventing gray hair from appearing or for treating gray hair,will be given hereinafter. The hydrosoluble constituents mayadvantageously be dissolved in the aqueous phase in which the lipidicpowder is dispersed, as indicated in Example 3. For example, theseconstituents may be incorporated, at least in part, in the liposomes.

EXAMPLE 12

Lotion reducing hair drop

    ______________________________________    Suspension of liposomes according to Example 4                             50 g    Carbopol 940 ®       0.03 g    distilled water, qsp     100 ml    ______________________________________

EXAMPLE 13

Anti-hair drop lotion

    ______________________________________    Suspension of liposomes according to Example 5                             50 g    Carbopol 940 ®       0.03 g    panthenol                0.1 g    keratin hydrolysat       0.2 9    hydrosoluble perfume     0.1 g    distilled water, qsp     100 ml    ______________________________________

This lotion is applied on the scalp twice a day for 6 months.

EXAMPLE 14

Lotion for stimulating the dermal papilla

    ______________________________________    Suspension of liposomes according to Example 6                             50 g    Carbopol 940 ®       0.04 g    Phytantriol              0.1 g    conserving agents        0.05 g    protein-zinc complex     0.1 g    water, qsp               100 ml    ______________________________________

Lotion promoting regrowth of the hair and preventing gray hair fromappearing

EXAMPLE 15

    ______________________________________    Suspension of liposomes according to Example 7                             50 g    Carbopol 940 ®       0.05    glucose tyrosinate       0.05    complex of oligo-elements                             0.1    theophylline             0.01    conserving agents        0.05    distilled water, qsp     100 ml    ______________________________________

This Lotion is applied in the evening on the scalp over the grayingareas and the zones where the hair has fallen, in a cure of 4 months.

EXAMPLE 16

hair loss preventing

    ______________________________________    Suspension of liposomes according to Example 8                             45 g    perfume                  0.1 g    Carbopol 940 ® gel at 1.5%                             50 g    distilled water, qsp     100 g    ______________________________________

Apply this gel, preferably after a shampoo, twice a week, in a cure of 2months.

EXAMPLE 17

    ______________________________________    Suspension of liposomes according to Example 9                             50 g    perfume                  0.1    protein-zinc complex     0.05    Carbopol gel at 1.5%     45 g    water, qsp               100 g    ______________________________________

This gel is preferably applied every evening over the areas of drop, ina cure of 4 months.

EXAMPLE 18

    ______________________________________    Suspension of liposomes according to Example 1                             20 g    Carbopol 940 ®       0.03 g    distilled water, qsp     100 ml    ______________________________________

EXAMPLE 19

Tanning gel

    ______________________________________    Suspension of liposomes (non-gelified) according to Example                                 50 g    Carbopol 940 ®           1.25 g    hydrosoluble solar filter    6 g    distilled water, qsp         100 g    ______________________________________

EXAMPLE 20

Lotion promoting regrowth of the hair

    ______________________________________    Suspension of liposomes according to Example 7 but containing                                 50 g    in the aqueous phase human keratin hydrolysate at a concentra-    tion of 5%    Carbopol 940 ®           0.05 g    Complex of oligo-element     0.1 g    conserving agent             0.05 g    distilled water, qsp         100 ml    ______________________________________

The suspension of liposomes according to Example 7 containing in theaqueous phase human keratin hydrolysate at 5%, is prepared in accordancewith Example 3 except that the lipidic film is taken up in an aqueoussolution containing 5% of human keratin hydrolysate.

This solution is applied in the evenings on the scalp in the areas ofhair loss, in a cure of 4 months.

As it is well known to those skilled in the art, liposomes represent aparticular embodiment of hydrated lipidic lamelar phases. Thus,according to the invention, the hydrated lipidic lamelar phases are in aspecific embodiment in the form of liposomes.

We claim:
 1. A method of promoting hair growth, reducing hair loss,comprising applying on the desired area to be treated comprising hairand scalp, a hair treating effective amount of at least one compositioncomprising hydrated lipidic lamellar phases or liposomes containing atleast in part a derivative of labdane of formula I herebelow: ##STR11##in which: R₁ and R₂ are identical or different and each represent ahydroxy group or an --O --CO--R₆ group in which R₆ represents an alkylradical having from 1 to 7 atoms of carbon, an alkocy radical havingfrom 1 to 7 atoms of carbon, or an alkenyl radical having from 1 to 7atoms of carbon, optionally substituted by one or more hydroxy or##STR12## groups in which R₇ and R₈ each represent an atom of hydrogen,an alkyl radical having from 1 to 4 atoms of carbon or R₇ and R₈represent together and with the atom of nitrogen, a heterocyclic radicalsuch as piperidino, morpholino, N¹ -methyl-piperazino;R₃ represents anatom of hydrogen or a hydroxy group; R₄ represents an atom of oxygen orthe assembly ##STR13## R₅ represents an ethyl or vinyl radical;optionally in a pharmaceutically or cosmetically acceptable excipient.2. The method of claim 1, wherein the labdane derivative is a componentof formula I in which:R₁ represents the hydroxy group; R₂ represents ahydroxy group or a --O--CO--R₆ group in which R₆ represents an alkylradical having from 1 to 4 atoms of carbon, an alkoxy radical havingfrom 1 to 4 atoms of carbon or an alkenyl radical having from 1 to 4atoms of carbon, possibly substituted by one or two hydroxy groups or,at one chain end, by a ##STR14## group in which R₇ and R₈ each representa methyl or ethyl radical or represent together and with the neighboringatom of oxygen, a heterocyclic radical such as piperidino, morpholino,N¹ -methylpiperazino; R₃ represents the hydroxy group, R₄ represents anatom of oxygen, R₅ represents the vinyl radical.
 3. The method of claim1, wherein said labdane derivative is selected from the group consistingof:forskoline 7-O-deacetyl-forskoline coleforsine7-O-deacetyl-7-β-O-propanoyl-forskoline7-O-deacetyl-7-β-O-(ethoxycarbonyl)-forskoline7-O-deacetyl-7-β-O-(propoxycarbonyl)-forskoline7-O-deacetyl-7-β-O-(2,3-dihydroxy-propanoyl)-forskoline7-O-deacetyl-7-β-O-(3-methyl-2-butenoyl)-forskoline 7-O-deacetyl-7-β-O-4-(N¹ -methyl-piperazino)-butanoyl!-forskoline7-O-deacetyl-7-β-O-(4-morpholino-butanoyl)-forskoline 6-β-O-3-piperidino-propanoyl)-forskoline 6-β-O-(piperidino-acetyl)-forskoline.4. The method of claim 1, wherein the concentration of said derivativeof labdane incorporated at least in part in hydrated lipidic lamellarphases or liposomes is added at a level of between 0.0001% and 1% byweight with respect to the total weight of the composition.
 5. Acosmetic composition comprising hydrated lipidic lamellar phases orliposomes or mixtures thereof, containing at least in part a derivativeof labdane, of formula I hereinbelow: ##STR15## in which: R₁ and R₂ areidentical or different and each represent a hydroxy group or an--O--CO--R₆ in which R₆ represents an alkyl radical having from 1 to 7atoms of carbon, an alkoxy radical having from 1 to 7 atoms of carbon,or an alkenyl radical having from 1 to 7atoms of carbon, optionallysubstituted by one or more hydroxy or ##STR16## groups in which R₇ andR₈ each represent an atom of hydrogen, an alkyl radical having from 1 to4 atoms of carbon such as ethyl or represent together and with the atomof a nitrogen a heterocyclic radical such as piperidino, morpholino, N¹-methyl-piperazino; R₃ represents an atom of hydrogen or a hydroxygroup; R₄ represents an atom of oxygen or the assembly ##STR17## R₅represents an ethyl or vinyl radical; and said composition being adaptedfor a topical application on the hair and scalp.
 6. The composition ofclaim 5, wherein the labdane derivative is a compound of formula I inwhich:R₁ represents the hydroxy group; R₂ represents a hydroxy group ora --O--CO--R₆ group in which R₆ represents an alkyl radical having from1 to 4 atoms of carbon, an alkoxy radical having from 1 to 4 atoms ofcarbon or an alkenyl radical having from 1 to 4 atoms of carbon,possibly substituted by one or two hydroxy groups or, at one chain end,by ##STR18## group in which R₇ and R₈ each represent a methyl or ethylradical or represent together and with the atom of nitrogen aheterocyclic radical such as piperidino, morpholino,N¹-methylpiperazino; R₃ represents the hydroxy group, R₄ represents anatom of oxygen, R₅ represents the vinyl radical.
 7. The composition ofclaim 5, wherein the labdane derivative is selected from the groupconsisting of:forskoline 7-O-deacetyl-forskoline coleforsine7-O-deacetyl-7-β-O-propanoyl-forskoline7-O-deacetyl-7-β-O-(ethoxycarbonyl)-forskoline7-O-deacetyl-7-β-O-(propoxycarbonyl)-forskoline7-O-deacetyl-7-β-O-(2,3-dihydroxy-propanoyl)-forskoline7-O-deacetyl-7-β-O-(3-methyl-2-butenoyl)-forskoline 7-O-deacetyl-7-β-O-4-(N¹ -methyl-piperazino)-butanoyl!-forskoline7-O-deacetyl-7-β-O-(4-morpholino-butanoyl)-forskoline 6-β-O-3-piperidino-propanoyl)-forskoline 6-β-O-(piperidino-acetyl)-forskoline.8. The composition of claim 5, wherein said composition comprises from0.0001 to 1% by weight, with respect to the total weight of saidcomposition.
 9. A cosmetic composition comprising hydrated lipidiclamellar phase or liposomes or mixtures thereof, encapsulating at leastin part an organic extract of Coleus, said composition being adapted fora topical application on the hair and scalp.
 10. The composition ofclaim 9, wherein said organic extract is an organic extract of roots ofColeus.
 11. The composition of claim 9, wherein said Coleus is the plantColeus forskohlii.
 12. The composition of claim 9, wherein said Coleusorganic extract is obtained by a process comprising at least one step ofextraction with ethyl acetate.
 13. The composition of claim 11, whereinsaid Coleus organic extract is obtained by a process comprising at leastone step of extraction with ethyl acetate.
 14. The composition of claim9, wherein the concentration of said organic extract of Coleus rangesbetween 0.0001% and 1% by weight, with respect to the total weight ofthe composition.
 15. The composition of claim 9, wherein said organicextract is obtained by extraction of the plant with an organic solvent,said organic solvent is selected from the group consisting of analkanol, a carboxylic acid ester, a dialkyl ketone, a dialkyl ether, anaromatic hydrocarbon, a halogenated aliphatic hydrocarbon and ahalogenated aromatic hydrocarbon.
 16. The composition of claim 15,wherein said alkanol is selected from the group consisting of methanoland ethanol; said aromatic hydrocarbon is selected from the groupconsisting of benzene, toluene and xylene; said halogenated aliphatichydrocarbon is selected from the group consisting of methylene chlorideand chloroform; said carboxylic acid ester is ethyl acetate.
 17. Thecomposition of claim 15, wherein said solvent extraction is effected ata temperature ranging between the ambient temperature and the boilingpoint of the organic solvent; the ratio of the Coleus plant with respectto the organic solvent is ranging between 1:5 and 1:20 part by weight.18. The composition of claim 15, wherein said extraction comprises anend extraction step with an alcohol.
 19. The composition of claim 18,wherein said alcohol is ethanol.
 20. The composition of claim 9, whereinsaid composition comprises from 0.01% to 1% by weight, with respect tothe total weight of the composition, of said Coleus extract.
 21. Amethod of treatment for preventing grey hair appearance and for thetreatment of grey hair comprising applying on the areas in need of saidtreatment, a treating effective amount of at least one compositioncomprising hydrated lipidic lamellar phases or liposomes encapsulating aColeus forskolli plant tissue extract obtained by extracting said Coleusforskolli plant with an organic solvent.
 22. A method according to claim21 wherein the composition is applied on the scalp in the areas in needof said treatment.
 23. A method of treatment for preventing grey hairappearance and for the treatment of grey hair, comprising applying onthe desired area to be treated comprising hair and scalp, a hairtreating effective amount of at least one composition comprisinghydrated lipidic lamellar phases or liposomes containing at least inpart a derivative of labdane of formula I herebelow: ##STR19## in which:R₁ and R₂ are identical or different and each represent a hydroxy groupor an --O--CO--R₆ group in which R₆ represents an alkyl radical havingfrom 1 to 7 atoms of carbon, an alkoxy radical having from 1 to 7 atomsof carbon, or an alkenyl radical having from 1 to 7 atoms of carbon,optionally substituted by one or more hydroxy or ##STR20## groups inwhich R₇ and R₈ each represent an atom of hydrogen, an alkyl radicalhaving from 1 to 4 atoms of carbon or R₇ and R₈ represent together andwith the atom of nitrogen, a heterocyclic radical such as piperidino,morpholino, N¹ -methyl-piperazino;R₃ represents an atom of hydrogen or ahydroxy group; R₄ represents an atom of oxygen or the assembly ##STR21##R₅ represents an ethyl or vinyl radical.
 24. The method of claim 23,wherein the composition is in a pharmaceutically or cosmeticallyacceptable excipient.
 25. The method of claim 23, wherein said labdanederivative is selected from the group consisting of:forskoline,7-O-deacetyl-forskoline, coleforsine,7-O-deacetyl-7-β-O-propanoyl-forskoline,7-O-deacetyl-7-β-O-(ethoxycarbonyl)-forskoline, 7-O-deacetyl-7-β-O(propoxycarbonyl)-forskoline,7-O-deacetyl-7-β-O-(2.3-dihydroxy-propanoyl)-forskoline,7-O-deacetyl-7-β-O-(3-methyl-2-butenoyl)-forskoline, 7-O-deacetyl-7-β-O-4-N¹ -methyl-piperazino)-butanoyl!-forskoline,7-O-deacetyl-7-β-O-(4-morpholino-butanoyl)-torskoline, 6-β-O-3-piperidino-propanoyl!-forskoline, and6-β-O-(piperidino-acetyl)-forskoline.
 26. The method of claim 23,wherein the concentration of said derivative of labdane incorporated atleast in part in hydrated lipidic lamellar phases or liposomes isbetween 0.0001% and 1% by weight with respect to the total weight of thecomposition.